Unravelling inclusion body myositis using a patient‐derived fibroblast model

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• dc.contributor.author Cantó-Santos, Judith
• dc.contributor.author Valls-Roca, Laura
• dc.contributor.author Tobías, Ester
• dc.contributor.author García-García, Francesc Josep
• dc.contributor.author Guitart-Mampel, Mariona
• dc.contributor.author Esteve-Codina, Anna
• dc.contributor.author Martín-Mur, Beatriz
• dc.contributor.author Casado, Mercedes
• dc.contributor.author Artuch, Rafael
• dc.contributor.author Solsona-Vilarrasa, Estel
• dc.contributor.author Fernandez-Checa, José Carlos
• dc.contributor.author García-Ruiz, Carmen
• dc.contributor.author Rentero, Carles
• dc.contributor.author Enrich, Carlos
• dc.contributor.author Moreno-Lozano, Pedro J.
• dc.contributor.author Milisenda, José César
• dc.contributor.author Cardellach, Francesc
• dc.contributor.author Grau-Junyent, Josep M.
• dc.contributor.author Garrabou, Glòria
• dc.date.accessioned 2023-05-23T06:11:50Z
• dc.date.available 2023-05-23T06:11:50Z
• dc.date.issued 2023
• dc.description Includes supplementary materials for the online appendix.
• dc.description.abstract Inclusion body myositis (IBM) is an inflammatory myopathy clinically characterized by proximal and distal muscle weakness, with inflammatory infiltrates, rimmed vacuoles and mitochondrial changes in muscle histopathology. There is scarce knowledge on IBM aetiology, and non-established biomarkers or effective treatments are available, partly due to the lack of validated disease models. We have performed transcriptomics and functional validation of IBM muscle pathological hallmarks in fibroblasts from IBM patients (n = 14) and healthy controls (n = 12), paired by age and sex. The results comprise an mRNA-seq, together with functional inflammatory, autophagy, mitochondrial and metabolic changes between patients and controls. Gene expression profile of IBM vs control fibroblasts revealed 778 differentially expressed genes (P-value adj < 0.05) related to inflammation, mitochondria, cell cycle regulation and metabolism. Functionally, an increased inflammatory profile was observed in IBM fibroblasts with higher supernatant cytokine secretion (three-fold increase). Autophagy was reduced considering basal protein mediators (18.4% reduced), time-course autophagosome formation (LC3BII 39% reduced, P-value < 0.05), and autophagosome microscopic evaluation. Mitochondria displayed reduced genetic content (by 33.9%, P-value < 0.05) and function (30.2%-decrease in respiration, 45.6%-decline in enzymatic activity (P-value < 0.001), 14.3%-higher oxidative stress, 135.2%-increased antioxidant defence (P-value < 0.05), 11.6%-reduced mitochondrial membrane potential (P-value < 0.05) and 42.8%-reduced mitochondrial elongation (P-value < 0.05)). In accordance, at the metabolite level, organic acid showed a 1.8-fold change increase, with conserved amino acid profile. Correlating to disease evolution, oxidative stress and inflammation emerge as potential markers of prognosis.These findings confirm the presence of molecular disturbances in peripheral tissues from IBM patients and prompt patients' derived fibroblasts as a promising disease model, which may eventually be exported to other neuromuscular disorders. We additionally identify new molecular players in IBM associated with disease progression, setting the path to deepen in disease aetiology, in the identification of novel biomarkers or in the standardization of biomimetic platforms to assay new therapeutic strategies for preclinical studies.
• dc.description.sponsorship This study was supported by Instituto de Salud Carlos III (ISCIII-FEDER, grants PI18/00498, PI18/00451 and PI21/00935) and co-funded by the European Union. Additionally, JC-S is supported by the APIF Programme (University of Barcelona), FJG-G by the CIBERER (ISCIII-FEDER), MG-M by CD21/00019 (ISCIII- FSE+), CR by the Serra Húnter Programme (Generalitat de Catalunya), RA by Torrons Vicens, JCF-C by PID2019-111669RB-I00, CG-R by PID2020-115055RB-I00 and AE-C by PT17/0009/0019 (ISCIII-MINECO-FEDER).
• dc.format.mimetype application/pdf
• dc.identifier.citation Cantó‐Santos J, Valls‐Roca L, Tobías E, García‐García FJ, Guitart‐Mampel M, Esteve‐Codina A, et al. Unravelling inclusion body myositis using a patient‐derived fibroblast model. J Cachexia Sarcopenia Muscle. 2023 Apr;14(2):964-77. DOI: 10.1002/jcsm.13178
• dc.identifier.doi http://dx.doi.org/10.1002/jcsm.13178
• dc.identifier.issn 2190-5991
• dc.identifier.uri http://hdl.handle.net/10230/56935
• dc.language.iso eng
• dc.publisher Wiley
• dc.relation.ispartof Journal of Cachexia, Sarcopenia and Muscle. 2023 Apr;14(2):964-77
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-111669RB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-115055RB-I00
• dc.rights © 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided theoriginal work is properly cited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Inclusion body myositis
• dc.subject.keyword Myopathy
• dc.subject.keyword Fibroblasts
• dc.subject.keyword Autophagy
• dc.subject.keyword Inflammation
• dc.subject.keyword Mitochondria
• dc.title Unravelling inclusion body myositis using a patient‐derived fibroblast model
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion